SUMMARY TRD1 will focus on the design and implementation of adaptive-responsive biomaterials to meet the goals of the P41. These are biomaterials that can sense and actuate cells or respond to the local environment to drive the functional restoration of complex tissue structures, in vitro and in vivo. The hypothesis is that biomaterial systems with integrated features for activation/response can provide specific benefits for designing scaffolds for restoration of tissue structure and function. These new material systems will be integrated with the needs and goals of the other TRDs to optimize tissue outcomes at both the fundamental and translational levels. The ultimate goal is to develop biomaterial systems for functional restoration of complex tissue structures based on the response to changes in the local environment (intrinsic signaling) or via applied changes (extrinsic signaling). The plans are to develop materials that provide adaptive responses to changes in local biology and conditions (e.g., pH, temperature reactive oxygen, enzymes) or to external signals (e.g., light, electric fields) to effect a change to improve tissue function or regeneration goals. Control of mechanical properties, degradation and release of bioactive factors to respond to local changes are examples of dynamic response-control goals. The core biomaterials will be based on biopolymers (e.g., elastins, collagens, silks, hyaluronic acid, others) as bioengineered variants and composites. Three specific aims will be pursued. Aim 1: Biomaterials that dynamically change properties in response to local signals. These biopolymer systems will provide core functions for sensing-response using silk-elastin chemistry and composite designs with hyaluronic acid and collagen, for a broad range of utility for different cell and tissue needs. Aim 2: Biomaterials that change properties on demand, in response to external stimuli. The focus will be on light activation systems (via specific chemistries) or electric field-mediated changes (via incorporated conductive components). The goal is to control the material volume, mechanics, and delivery of bioactive factors in an on-demand mode, using external sources (light, electric field), to control cell and tissue outcomes. Aim 3: ?Smart? scaffolds for tissue regeneration and modeling of disease. Scaffold designs based on the materials from Aims 1 and 2 will be utilized to generate functional devices and tissue models for studies in TRD1, 2 and 3, in vitro and in vivo.